The availability of a model for lentivirus immunosuppression is likely to be of critical importance in the generation and testing of an effective vaccine against HIV and AIDS. The macaque/simian immunodeficiency virus (SIV) model is perhaps the most appropriate, since it involves a lentivirus capable of induction of fatal immunodeficiency disease, and SIV is the closest known relative of HIV-l and especially HIV-2. Three of the basic problems which currently limit our understanding of immunodeficiency disease induction, the development of the SIV model, and an HIV vaccine will be addressed: (1) The in vivo biological activity of only a single molecular clone of SIV has been extensively evaluated thus far, and it appears to be minimally pathogenic in macaques, thus there is to date no adequate disease-induction system involving a molecularly defined pathogen: (2) knowledge of the features of lenti-immunodeficiency viruses responsible for their pathogenicity, and; (3) the reported high degree of genetic variation of lenti- immunodeficiency virus genomes could result in immunological escape of mutant virus in infected individuals vaccinated with a prototype inoculum of limited variability. We propose to identify and molecularly define an acute SIV pathogen starting with virus from three sources: (1) SIVsmm-PBj14, the parental strain of which induces fatal disease with survival times as short as one week: (2) SIVDelta-B670, the parental strain of which induces fatal immunodeficiency disease in 2-4 months: and (3) SIVmac-BK28, in vivo passaged from an animal which died 17 months following inoculation with this molecularly cloned and sequenced virus. We then propose to identify the viral genetic sequences responsible for disease induction by generation and testing of virus chimeras between an acute pathogen and a minimally pathogenic strain, such as SIVmac-BK28. To evaluate the rate of genome diversity we propose to inoculate macaques with molecularly cloned SIV, then monitor infected peripheral blood mononuclear cells for variation in viral genome sequence. Viral sequences will be amplified using the "polymerase chain reaction", then cloned in M13 bacteriophage to determine their nucleotide sequence and, therefore, their sequence divergence. The rate of evolution of immunologically divergent epitopes will be determined in Dr. Bruck's project.